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. 2014 Feb;66(2):309-22.
doi: 10.1111/jphp.12129. Epub 2013 Aug 20.

Formulation optimization of hot-melt extruded abuse deterrent pellet dosage form utilizing design of experiments

Sindhuri Maddineni  1 , Sunil Kumar Battu, Joe Morott, Majumdar Soumyajit, Michael A Repka
Affiliations

Formulation optimization of hot-melt extruded abuse deterrent pellet dosage form utilizing design of experiments

Sindhuri Maddineni et al. J Pharm Pharmacol. 2014 Feb.

Abstract

Objective: The objective of this study was to develop techniques for an abuse-deterrent (AD) platform utilizing the hot-melt extrusion (HME) process.

Methods: Formulation optimization was accomplished by utilizing Box-Behnken design of experiments to determine the effect of the three formulation factors: PolyOx WSR301, Benecel K15M and Carbopol 71G; each of which was studied at three levels on tamper-resistant (TR) attributes of the produced melt extruded pellets. A response surface methodology was utilized to identify the optimized formulation. Lidocaine hydrochloride was used as a model drug, and suitable formulation ingredients were employed as carrier matrices and processing aids.

Key findings: All of the formulations were evaluated for the TR attributes, such as particle size post-milling, gelling and percentage of drug extraction in water and alcohol. All of the design of experiments formulations demonstrated sufficient hardness and elasticity, and could not be reduced into fine particles (<150 μm), which is a desirable feature to prevent snorting. In addition, all of the formulations exhibited good gelling tendency in water with minimal extraction of drug in the aqueous medium. Moreover, Benecel K15M, in combination with PolyOx WSR301, could be utilized to produce pellets with TR potential.

Conclusion: HME has been demonstrated to be a viable technique with a potential to develop novel AD formulations.

Keywords: abuse-deterrent; design of experiment; hot-melt extrusion; insufflation; optimization.

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Figures

Figure 1
Figure 1
Hardness evaluation of the preliminary melt-extruded pellet formulations. The extrudates prepared from PEO-301 (pure PolyOx WSR 301) could only be deformed, but not broken during the hardness evaluation.
Figure 2
Figure 2
Drug extraction in alcohol from the preliminary melt-extruded pellet formulations. + indicates that the pellets made of PEO-301 could not be milled into fine powder. Hence, this sample was not tested for drug extraction in alcohol from the hot-melt extruded pellets.
Figure 3
Figure 3
Drug release from the preliminary melt-extruded pellet formulations.
Figure 4
Figure 4
Visual comparison of different hot-melt extrusion pellet formulations before and after particle size reduction.
Figure 5
Figure 5
Response surface regression after model reduction obtained using ‘percent active pharmaceutical ingredient extracted in water’ as a response.
Figure 6
Figure 6
Response surface regression after model reduction obtained using ‘percent active pharmaceutical ingredient extracted in alcohol’ as a response.
Figure 7
Figure 7
(a) Standardized residual plots on the final reduced models for percent active pharmaceutical ingredient extracted in water as the response. (b) Standardized residual plots on the final reduced models for percent active pharmaceutical ingredient extracted in alcohol as the response.
Figure 7
Figure 7
(a) Standardized residual plots on the final reduced models for percent active pharmaceutical ingredient extracted in water as the response. (b) Standardized residual plots on the final reduced models for percent active pharmaceutical ingredient extracted in alcohol as the response.
Figure 8
Figure 8
(a) Response optimization plot for the HPMC (the only significant factor) with percent active pharmaceutical ingredient extracted in water as a response. (b) Response optimization plot for the HPMC (the only significant factor) with percent active pharmaceutical ingredient extracted in alcohol as a response.
Figure 8
Figure 8
(a) Response optimization plot for the HPMC (the only significant factor) with percent active pharmaceutical ingredient extracted in water as a response. (b) Response optimization plot for the HPMC (the only significant factor) with percent active pharmaceutical ingredient extracted in alcohol as a response.
See this image and copyright information in PMC

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